Reversible Kallmann Syndrome, Delayed Puberty, and Isolated Anosmia Occurring in a Single Family with a Mutation in the Fibroblast Growth Factor Receptor 1 Gene
Abstract
Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder. Recently, loss-of-function mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been shown to cause autosomal dominant KS. To date, the detailed reproductive phenotype of KS associated with mutations in the FGFR1 has yet to be described. We report a kindred comprising a male proband with KS and spontaneous reversibility, whose mother had delayed puberty and whose maternal grandfather isolated anosmia. The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy. Upon discontinuation of T therapy, he recovered from his hypogonadotropic hypogonadism, as evidenced by a normal LH secretion pattern, sustained normal serum T levels, and active spermatogenesis. The three members of this single family harbor the same FGFR1 mutation (Arg622X) in the tyrosine kinase domain. This report demonstrates 1) the first genetic cause of the rare variant of reversible KS, 2) the reversal of hypogonadotropic hypogonadism in a proband carrying an FGFR1 mutation suggests a role of FGFR1 beyond embryonic GnRH neuron migration, and 3) a loss of function mutation in the FGFR1 gene causing delayed puberty.
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Reversal of IHH after testosterone treatment has been reported in a patient with a heterozygous FGFR-1 Arg622X mutation.
“Reversal of IHH after testosterone treatment has been reported in a patient harboring a heterozygous mutation in the tyrosine kinase domain of FGFR-1 (Arg622X).”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [19]
Reversal of IHH in the FGFR-1 Arg622X case suggests that FGFR-1 might regulate reproduction beyond embryonic GnRH neuronal migration.
“Reversal of IHH in this case suggests that FGFR-1 might regulate reproduction beyond the stage of embryonic GnRH neuronal migration.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [19]
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- Authors
- Pitteloud, N., Acierno, J. S., Meysing, A. U., Dwyer, A. A., Hayes, F. J., & Crowley, W. F.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Pitteloud, Nelly
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-03-01
- Volume
- 90
- Issue
- 3
- Pages
- 1317-1322
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1964741660
- Cited by
- 160
- References
- 40
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 13 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 12
- FWCI
- 13.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health (5r01dk003892-40)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-03892)
- National Center for Research Resources (M01RR001066, M01-RR01066)
- NIH Clinical Center
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD15788, R01HD015788, U54HD029164, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- Kallmann syndrome, FGFR1 mutation, FGFR1, delayed puberty, hypogonadotropic hypogonadism, testosterone replacement therapy, loss-of-function mutations, tyrosine kinase domain, spermatogenesis, GnRH neuron migration, autosomal dominant inheritance, familial kindred
- MeSH terms
- Adult, Amino Acid Sequence, Androgens, Olfaction Disorders, Family Health, Humans, Hypothalamo-Hypophyseal System, Gonadotropin-Releasing Hormone, Male, Molecular Sequence Data, Neurons, Pedigree, Pituitary-Adrenal System, Puberty, Delayed, Testosterone, Kallmann Syndrome, Receptors, Fibroblast Growth Factor, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1
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